AU697187B2

AU697187B2 - Pharmaceutical, orally applicable composition

Info

Publication number: AU697187B2
Application number: AU37945/95A
Authority: AU
Inventors: Manfred Durr; Benedikt Gajdos
Original assignee: Rhone Poulenc Rorer GmbH
Current assignee: Sanofi Aventis Deutschland GmbH
Priority date: 1994-12-10
Filing date: 1995-11-20
Publication date: 1998-10-01
Anticipated expiration: 2015-11-20
Also published as: ZA9510427B; TW449483B; EP0715857A3; EP0715857A2; DE4444051A1; AU3794595A; JPH08208520A; MX9505065A; US6008249A; KR100408582B1; KR960021060A; CA2164777A1

Description

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AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

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Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: Rhone-Poulenc Rorer GmbH Nattermannallee 1 50829 Koln

GERMANY

Benedikt Gajdos and Manfred Durr Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Wales, 2000, Australia Pharmaceutical, Orally Applicable Composition a *o

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*Uc a a The following statement is a full description of this invention, including the best method of performing it known to me/us:a a

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Ct 5845 lu rZ Pharmaceutical, Orally Applicable Composition The present invention concerns a pharmaceutical, orally applicable composition, whereby said solid composition contains at least one active ingredient selected from the group consisting of an analgesic, an antirhieumatic agent or a mixture thereof, at least one disintegrant selected from the group consisting of starch, a starch derivative, cellulose, a cellulose derivative, alginic acid, an alginic acid derivative, casein, a casein derivative, an insoluble polyvinylpyrrolidone and mixtures thereof, as well as at least one usual pharmaceutical additional ingredient, whereby said composition furthermore contains at least one ingredient accelerating the decomposition of said composition in the mouth or in lo a liquid, whereby this ingredient is a water-soluble amino acid, a water-soluble amino acid derivative and/or a water-soluble salt of an amino acid and whereby said composition contains said ingredient in such a concentration that said composition decomposes in the mouth or in a liquid within one second up to thirty seconds.

Solid, orally applicable pharmaceutical compositions that contain at least one active 1ingredient, at least one disintegrant, as well as at least one pharmaceutically usual additional ingredierit, are known for a long time and available on the trade market, Depending on the respective active ingredient and/or the active ingredient mixture, said V known compositions are used as tablets, granular powder or powder in order to prevent and/or to treat pain of all sorts, especially for the treatment of headaches, rheumatic pain, pain in the limbs, migraine, toothaches, as well as for the treatment or rheumatic afflictions, gout, non-rheumatic painful swelling and/or infections. In general therefore it is required that the patient swallows the corresponding tablet or granular powder Ott, unchewed which is difficult with large tablets, or that the patient chews said tablet or :11, 25granular powder before swallowing, which often leads to a conglutination of components 26of said tablet and/or granular powder in the dental and/or p,09atal area of the mouth, The removal of said conglutinated components causes problems arnd furthermore releases the active ingredient in the course of time, which after all then causes a very unpleasant taste in the mouth. In order to avoid the above described problems with the application of said known pharmaceutical compositions, specifically produced taM-.ts are known that inevitably decompose relatively fast in the mouth or in a corresponding liquid, so that hereby the chewing in the mouth of said known tablets that usually is also named Lyoc-tablets, can be omitted. Such specific and known pharmaceutical compositions have however the handicap that they can be slightly and undesirably damaged while being produced, while being transported or while being applied to the patient, so that also their use is correspondingly limited.

The aim of the present invention is to make disposable such an orally applicable, solid composition that on one side shows a particular high stability and on the other side decomposes very fast while being applied.

Said aim. is realised, according to the invention, by a pharmaceutical, orally 4pplicable composition, whereby said solid composition contains at least one active IN.WSHI10182:KBM 1 2 ingredient selected from the group consisting of an analgesic, an antirheumatic agent or a mixture thereof, at least one disintegrant selected from the group consisting of starch, a starch derivative, cellulose, a cellulose derivative, alginic acid, an alginic acid derivative, casein, a casein derivative, an insoluble polyvinylpyrrolidone and mixtures thereof, as well as at least one usual pharmaceutical additional ingredient, whereby said composition furthermore contains at least one ingredient accelerating the decomposition of said composition in the mouth or in a liquid, whereby this ingredient is a water-soluble amino acid, a water-soluble amino acid derivative and/or a water-soluble salt of an amino acid and whereby said composition contains said ingredient in such a concentration that said composition decomposes in the mouth or in a liquid within one second up to thirty seconds.

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IN:\LIBHIO182 KRML I k* 3 The inventive pharmaceutical and orally applicable solid composition contains at least one active ingredient, at least one disintegrant, as well as at least one pharmaceutically usual additional ingredient. Furthermore said inventive composition contains at least one ingredient that accelerates the decomposition of said composition in the mouth or in a liquid, whereby said ingredient is a water-soluble amino acid, a water-soluble amino acid derivative and/or a water-soluble salt of an amino acid.

Surprisingly it was observed that said composition shows a very high decomposition rate, caused by the above indicated at least one ingredient (water-soluble amino acid, watersoluble amino acid derivative and/or a water-soluble salt of an amino acid), which means that, relatively to the time, said composition shows a high decomposition when it gets in contact with saliva (spittle) or an appropriate liquid, especially water. This again leads to a very fast i i •t decomposition (disintegration) of said inventive composition in the mouth, without being required to chew r ,said inventive composition. Therefore there are no problems concerning said inventive composition, as there are known in connection with the compositions according to the prior art and also incorporate with such known compositions that contain a disintegrant. That means that the components of et said inventive composition do not deposit in areas of the mouth-that are difficult to reach and therefore do not ~II~CII~ IL 4 cause an unwanted conglutination on the tongue and/or on -the palate and/or in the dental area, so that correspondingly said inventive composition does not cause a bitter taste during the application of said composition in the patient's mouth, caused by the release of the active ingredient. Furthermore the above mentioned ingredient (water-soluble amino acid, water-soluble amino acid derivative and/or a water-soluble salt of an amino acid) accelerating the decomposition of said inventive composition in the mouth or in a liquid, does not deteriorate the stability of said composition, so that also said inventive composition is not undesirably damaged Vduring its production, transport and application, so that correspondingly the complaint rate regarding said inventive composition particularly low. Also said inventive composition can be manufactured particularly low-priced by .conventional manufacturing techniques, while contrarily l's this is not the case concerning the known and above mentioned Lyoc-tablets.

i The above indicated high decomposition rate of the K inventive composition is referred to a synergistic effect of the at least one disintegrant with the ingredient ia~tr S (water-soluble amino acid, water-soluble amino acid derivative and/or water-soluble salt of an amino acid) itt* Basically the inventive composition can contain each watersoluble amino acid, each water-soluble amino acid derivative and/or each water-soluble salt of an amino acid, if it is secured that the above indicated ingredients that accelerate the decomposition of said inventive composition in the mouth and/or in a liquid, are not toxic, and do not show interaction with the at least one active ingredient.

It is particularly suitable, if the inventive composition contains the ingredient glycine, glycine derivative and/or a salt of glycine, that accelerate the decomposition of said inventive composition, whereby the term glycine derivative includes particularly ester, preferably of C 1

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4 -alcohols, and/or amides of glycine, preferably of C 1

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10 -carboxylic acids, and the term salts of glycine includes preferably water-soluble alkalisalts and/or alkaline earth salts, as well as the corresponding ammonium salts. These above described embodiments of the inventive composition that contain as ingredient glycine, a glycine derivative, a salt of glycine and/or their mixture, are 41 *b 20 toxicologically seen absolutely unobjectionable, whereby, caused by the relatively low price of the above indicated S ingredients basing on glycine, the embodiment of the inventive composition is manufacturable to a particular low S price.

Another embodiment of the inventive pharmaceutical composition contains such ingredients accelerating the I- l-~C-~a jMjjjjjjbr aIM r 6 decomposition (disintegration) of the inventive composition, additionally to above described ingredients basing on glycine, or instead of the ingredients basing on glycine, said accelerating ingredients are chosen from the group consisting of proline, hydroxy proline, lysine, the salts thereof and/or derivatives thereof. Hereby the term salts and the term derivatives include the salts and derivatives indicated above together with the glycine, whereby however concerning the proline, respectively the hydroxy proline, it is possible to correspondingly substitute the pyrrolidine-ring, particularly to halogenate it and/or to provide at the pyrrolidine-ring an additional

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2 -group, a N0 2 -group and/or a S0 3 H-group. Also one or more of the above mentioned substitutes can be arranged at the non-substituted CH 2 -groups of the lysine.

Concerning the previous and exactly described ingredients of the inventive composition that accelerate the decomposition of the inventive composition in the mouth 420 and/or in a liquid, it is to be noted that the inventive Scomposition contains the ingredients in such a concentration that the composition decomposes (disintegrates) in the mouth, respectively in a chosen S liquid within one second up to sixty seconds, preferably within one second up to thirty seconds.

AAr fl -t ~IpL_~41-- I_ 7 Depending on each active ingredient and on the usual additional ingredients, as well as on the composing of said composition, the concentration of the ingredient, respectively of the ingredient-mixture varies in said composition between 1 by weight and 90 by weight, particularly between 20 by weight and 70 by weight, corresponding to the composition ready to use.

As disintegrants the inventive composition contains preferably starch, a starch derivative, cellulose, a cellulose derivative, alginic acid, an alginic acid derivative, casein, a casein derivative and/or an waterinsoluble polyvinylpyrrolidone (crosspolyvidone). The above mentioned starch is particularly a corn- or a potato starch, the above mentioned starch derivative is particularly modified starch and/or sodium carboxymethyl starch, the above mentioned cellulose derivative is a* 44 particularly carboxymethyl cellulose and/or sodium carboxymethyl cellulose. Furthermore, appropriate :20 disintegrants are cross-linked casein, sodium salt of alginic acid, as well as polyvinylpyrrolidone insoluble in 4 saliva and/or water, whereby the latter mentioned product is also available on the market under the trade name Kollidon CL and Polyplasdone XL.

Concerning the concentration of the disintegrant in the inventive composition it is to be noted that it varies *1 P--(ll S- ls~SIIL~CI- ~-anrar~ru~---arul ra~-~--rr~-arc between 1 by weight and 50 by weight, preferably between 3 by weight and 20 by weight corresponding to the composition ready to use (apply).

A especially favorable further development of the above described embodiment of the inventive composition provides that hereby the inventive composition contains the at least one active ingredient in the form of active ingredient particles that are proportionately dispersed in the solid composition. Such a further development of said composition has next to a perfect stability, next to a particularly fast decomposition rate, also a specifically high efficacy.

One reason for this is that after the decomposition of the inventive composition the each active ingredient particle reaching the stomach, respectively the intestines (bowels), has a relatively large surface, so that they can cause correspondingly fast the desired therapeutic effects.

o Concerning the active ingredient or the active ingredient '4 20 mixture of the inventive composition it is to be noted that they are usual pharmaceutical active ingredients or active ingredient mixtures. Said, composition preferably contains such active ingredient or active ingredient mixtures that usually are found in known anti-cancer agents, antibiotics, antipyretic agents, immunostimulators, immunosuppressants, anti-inflammatory agents, anti-epileptic agents, agents for the treatment of cerebral affections, antihistamines, I r~-31qf ql~aClp~- C 00&e 1.550 i- C diuretics, hypotensors, antidiabetics, muscle relaxants, anti-ulcus agents, antidepressants, anti-allergic agents, cardiac-stimulating agents, vasodilators, anti-coagulant agents, antitussives and/or anti-cold agents as well as vitamins.

Particularly preferred in the sense of the present invention is a composition that contains an active ingredient with anti-inflammatory, anti-rheumatic or analgetic characteristics. Preferably the active ingredient or the active ingredient mixture is then synthesized on the base of a pyrazolone compound, a salicylic acid compound, a phenylbutanzone compound, a paracetamol compound, an antranilic acid compound, an arylic acetic compound and/or an aryl propionic acid compound.

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ft (C C To the inventive pharmaceutical composition concretely belong such compositions that contain as active ingredient or active ingredient mixture, ibuprofene, ketoprofene, 20 naproxene, tolmetine, furabiprofene, indomethacine, mefenamic acid, flufenamic acid, paracetamole, acetylsalicylic acid, alclofenac, ketoprofene, ibuprofene, and/or diclofenac-sodium, whereby the first mentioned active ingredients are found, when the inventive composition is supposed to be used as analgetic drug, and the latter mentioned four active ingredients are found in b; i ir rr tt I

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t i the inventive composition, when the inventive composition is used as an anti-rheumatic drug.

Concerning the concentration of the active ingredient and preferably the above mentioned active ingredients of the inventive composition is to be noted that this concentration of the active ingredient or of thPe active ingredient mixture varies between 1 by weight and 50 by weight, preferably between 15 by weight and 40 by weight, each corresponding to the inventive composition ready to use- Especially then, when the inventive composition contains as an active ingredient a hydrophilic active ingredient, it is recommendable to provide said hydrophilic active ingredient with a hydrophobic coating-layer and/or to embed said hydrophilic active ingredient into a hydrophobic matrix.

This embodiment of the inventive composition does not only show the already previous mentioned advantages (high decomposition rate, sufficient hardness and resistance), but also is characterized in that during the decomposition of the inventive composition in the mouth the active ingredient or the concrete active ingredient particles is and/or are prevented from forming large agglomerates by the hydrophobic coating-layer and/or the hydrophobic matrix, which would avoid the desired fine dispersion of the active ingredient. Furthermore, by such a hydrophobic coating- I i I, I I I

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_iili. ii.i i~ll-CI(I lie -II- IIUIL1I-~ layer and/or hydrophobic matrix is achieved that a bitter or unpleasant taste possibly caused by the active ingredient is suppressed.

The above mentioned suppression of the bitter and/or unpleasant taste of said active ingredient can also be achieved for the reason that the inventive composition contains an active ingredient and/or an active ingredient mixture that is nor provided with hydrophobic coating-layer and/or embedded into a hydrophobic matrix, but instead contains larger, previously consolidated active ingredient particles. By such a consolidation, specifically by a cczpression, of the active ingredient particles to larger agglomerates, the disposable surface is decreased in comparison to the actual active ingredient particles, so that correspondingly the decomposition procedure of said active ingredient in the mouth is delayed, which again suppresses an unpleasant or bitter taste.

(t I B rrr cr ~CLi I I; jt~ Ir Ir a 1 1 For the above mentioned coating and/or embedding of said active ingredient and/or said active ingredient mixture in a hydrophobic matrix, basically all coating substances and/or embedding substances can be chosen, that on one side secure the unwanted hydrophobization of the active ingredient and/or the active ingredient mixture and on the other side are toxicologically unobjectionable. Heretofore especially coating-layers and/or embedding substances are

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IRN: 318000 INSTR CODE: 51305 *1' jlb/5457M J11T 12 considered that are chosen from the group consisting of shellac, stearic acid, gelatine, zein, gum arabic, cellulose derivatives, polymere acrylic acid derivatives and/or polymere vinylacetates. To be mentioned concretely are methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, celluloseacetate-phthalate, hydroxypropylmethylcellulosephthalate, as well as polymere acrylic acid derivatives, particularly copolymerisates from methacrylic acids and esters from methacrylic acids; acrylic acid ethylmethacrylic acid methylester-copolymerisates; methacrylic acid-acrylic acid methylester-copolymerisates; acrylic- and methacrylic acid ester-copolymerisates with trimethylammoniummethacrylate; copolymerisates from dimethylaminomethacrylic acid and neutral methacrylic acid esters; vinylpyrrolidone-vinylacetate-copolymerisates; polyvinylacetate; polyvinylpyrrolidone as well as polyethylenglycol.

20 Concerning the amount of the above mentioned coatingand/or embedding substances it is to be noted that this amount of said coating- and/or embedding substances depends on the concentration of the corresponding hydrophilic active ingredient and/or the hydrophilic active ingredient mixture. The amount of said substances varies between 1 by weight and 10 by weight corresponding to the inventive composition ready to use.

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9;rl 9;11 13 Furthermore the inventive composition contains pharmaceutically usual additional ingredients, which are in particular bulkages, binders, lubricants, humectants, absorbents, antistatic substances, colouring substances and flavouring substances.

In particular the inventive composition contains pharmaceutically usual bulkages and binders, in a concentration between 0 by weight and 60 by weight.

Further it contains povidone, sugar, sugar alcohols and/or polyethylenglycol in a concentration between 0 by weight and 10 by weight each, as well as an usual concentration of flavouring substances, particularly of sweetening substances and/or aromatics. The usual flavouring substances that are found in the inventive composition were in particular ascorbic acid, tartaric acid, fumaric acid and/or citric acid, preferably ascorbic acid because ascorbic acid additionally functions as vitamin C.

t c As already previous mentioned the inventive pharmaceutical composition is solid and exists preferably as a tablet or granular powder. However, it is of course possible to manufacture the inventive composition in The form of a relatively coarse-grained powder.

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5845, 14 The disintegration accelerating ingredient is preferably glycine, a glycine derivative and/or a glycine salt, proline, hydroxy proline and/or lysine, a salt and/or a derivative thereof, especially in such a concentration that said composition decomposes in the mouth or in a liquid within one second up to sixty seconds, preferably within one second up to thirty seconds. For example, in a concentration between I by weight and 90 by weight, preferably in a concentration between 20wt% and The disintegrant is preferably starch, a starch derivative, cellulose, a cellulose derivative, alginic acid, an alginic acid derivative, casein, a casein derivative and/or an insoluble polyvinylpyrrolidone. The disintegrant is preferably in a concentration between lwt% and 50wt%, more preferably between 3wt% and It is preferred that the composition contains at least one active ingredient as active ingredient particles uniformly dispersed in the solid composition. The active ingredient is preferably a pyrazalone compound, a salicylic acid compound, a phenylbutazone compound, an anthranilic acetic compound, an aryl-acetic compound and/or an aryl-propionic acid compound an analgesic and/or an antirheumatic agent paracetamol, acetylsalicylic acid, ketoprofen, ibuprofen and/or diclofenac-sodium. The active ingredient may be in a concentration between Iwt% and 50wt%, more preferably between 15wt% and It is preferred that the composition contains at least one hydrophilic active ingredient provided with a hydrophobic coating layer and/or at least one hydrophilic active ingredient being embedded in a hydrophobic matrix. The hydrophobic coating layer and/or said matrix may comprise shellac, stearic acid, gelatine, zein, gum arabic, cellulose derivatives, polymer acrylic acid derivatives and/or polymer vinylacetates.

giot" The composition may contain as additional ingredient up to 60wt% bulkages and/or S, binders, up to 10wt% of at least one substance of povidone, sugar, sugar alcohols, polyethyleneglycol as well as usual sweetening agents and/ or aromatics.

The composition may be in the form of a tablet or a granular powder.

The inventive composition is explained more precisely in the examples. Hereinafter in e the examples the terms consolidation, spray-drying, hydro-granulation are used.

s By the term consolidation a procedure is meant in which the active ingredient and/or the active ingredient mixture is consolidated with a concrete additional ingredient and/or additional ingredient mixture mentioned in the examples, possibly by the addition of water, with an appropriate device, specifically a consolidating roller or a tablet compressor.

Thereafter the concreted material is crushed and if necessary dried. Should the portion of fine grains in the said concreted material be to high, particularly under 80Om, then said portion can be removed by being sieved.

By the term spray-drying a procedure is meant in which the active ingredient and/or the active ingredient mixture is dissolved or dispersed in water. Hereby the additional ingredients mentioned concretely in the examples, are added. Thereafter the dispersion and/or solution is dried lN:'UBCtI111:JOC in a spray tower in a stream of warm air with a product temperature between 30 OC and 120 OC.

By the term hydrogranulation a procedure is meant in which the active ingredient and/or the active ingredient mixture is granulated in an appropriate device, particularly in a mixer and/or a fluid bed granulator, during addition of the additional ingredients mentioned in the examples. Depending on the chosen active ingredient and the additional active ingredients the granular powder can be coated with an appropriate polymer.

When the products, submitted to the spray-drying, the hydrogranulation and the consolidation, are coated with an appropriate polymer which is in the following examples the product Eudragit E12,5, then this is marked in the following quoted examples by indicating the above mentioned It product.

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i 20 For the following components named in the examples with m their trade names Polyplasdone XL (GAF, USA), Aspartam (Nutra Sweet), Kollidon 25 (BASF), Acesulfam K (Hoechst), and Eu6ragit L (R6hm), Aerosil 200 (Degussa), Biogapress S 3326 (Gattefossg), the manufacturers are indicated in brackets after each component.

*1 16 Example 1 Manufacturing of a tablet with the active ingredient ketoprofene A mixture containing water and g g ketoprofene ethylcellulose was granulated and dried. After the drying and the sieving of the dried granular powder over a sieve with a mesh size of 1 mm, the following components were added 15 *t 44 4 4444b 4 4 44PE 44f 119 g 10 g i g g 1 g 2 g 2 g glycine, Polyplasdone XL, silica, aromatics, sodium chloride, sweetening substances and magnesium stearate.

4 C 20 S .The homogenised mixture was compressed to tablets weighing 200 mg. The tablet that way manufactured was named tablet 1.

I I~ 17 Example 2 Manufacturing of a tablet with the active ingredient ibuprofene A mixture containing water and 400 g ibuprofene g gelatine was granulated and dried. After the sieving and the drying of the dried granular powder over a sieve with a mesh size of 1 mm, the following components were added 405 g glycine, 15 40 g Polyplasdone XL, 20 g aromatics, 3 g silica, 1 g sodium chloride, 2 g sweetening substances and I "20 9 g magnesium stearate.

1 oThe homogenised mixture was compressed to tablets weighing .200 mg. The tablet that way manufactured was named tablet 2.

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18 Example 3 Manufacturing of a tablet with the active ingredient loperamide Although loperamide is a hydrophilic active ingredient, it was renounced on the providing of said active ingredient with a hydrophobic coating-layer, caused by the concentration of said active ingredient being relatively low.

A mixture containing 44. 4 .:~15 *444 4 c 4 9CC 9444O I 2 2 g 87,5 g 5 g 0,3 g 5 g Sg Sg loperamide HCL, glycine, Polyplasdone XXL, silica, aromatics, sweetening substances and magnesium stearate 9C4444 4 9: 44 4 C 4 44L was manufactured. From the correspondingly homogenised mixture tablets weighing 100 mg were compressed that are named tablets 3.

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i."i 001 11 19 Example 4 Manufacturing of a tablet with the active ingredient acetylcysteine A mixture containing water and 600 g g acetylcysteine, ethylcellulose was granulated and dried. After the drying and the sieving of the dried granular powder over a sieve with a mesh size of 1 mm, the following components were added $Ott 9 *1 ot 490 g 55 g Sg Sg g 3 g 10 g glycine, Polyplasdone XL, Aspartam, saccharine-sodium, aromatics, silica and magnesium stearate.

*t 1 2 t cr" It~ 991( 9 9 99 The homogenised mixture was compressed to tablets weighing 1.200 mg. The tablet that way manufactured was named tablet 4.

Example Manufacturing of a tablet with the active ingredient thyme extract A mixture containing water and 62,5 g thyme (taim) dry extract, 4 g Eudragit L was granulated and dried. After the drying and the sieving of the dried granular powder over a sieve with a mesh size of 1 mm, the following components were added 160 g glycine, 19 g Polyplasdone XL, 0,5 g silica, g aromatics, g liquiritiae succus powder, 1 g sweetening substances and 3 g magnesium stearate.

The homogenised mixture was compressed to tablets weighing 300 mg. The tablet that way manufactured was named tablet 5. The previous mentioned water can also be replaced by a non toxic solvent for Eudragit.

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21 Example 6 Manufacturing of a tablet with the active ingredient in form of an extract of the echinacea angustifolia A mixture containing water and 8 g 0,8 g extract rad. echinaceae angustifoliae, methyl-hydroxypropyl-cellulose was granulated and dried. After the drying and the sieving of the dried granular powder over a sieve with a mesh size of 1 mm, the following components were added .4 3I4 4 a," 4 4. 4 *4 *r 1t 4 120,7 g 8 g 0,5 g 8 g i g 3 g glycine, Polyplasdone XL, silica, aromatics, sweetening substances and magnesium stearate.

444444 t 4t ie 4t 444 4; 4 The homogenised mixture was compressed to tablets weighing 150 mg. The tablet that way manufactured was named tablet 6 a, i' l--aar~ Example 7 Manufacturing of a tablet with the active ingredient carbocysteine A mixture containing water and 375 g carbocysteine, 11,6 g gelatine was granulated and dried. After the drying and the sieving of the dried granular powder over a sieve with a mesh size of 1 mm, the following components were added 371,7 g glycine, 30 g Polyplasdone XL, g Aerosil, 1 g Aspartam powder, g Acesulfam K, 0,16 g orange aromatic and 4 g magnesium stearate.

The homogenised mixture was compressed to tablets weighing 810 mg. The tablet that way manufactured was named tablet 7.

23 Example 8 Manufacturing of a tablet with the active ingredient paracetamol A first mixture was manufactured containing 81,95 g glycine and 2 g Kollidon Furthermore a second mixture was manufactured containing i r 1 e 15 I 106,95 g Rhodapap NCR (paracetamol coated with ethylcellulose), 6 g Polyplasdone XL and 1 g -Aerosil 200.

From the components t c f 0,2 g 0,3 g 0,6 g 0,2 g Aspartam powder, Acesulfam-K, aromatic type peppermint sodium chloride a third mixture was manufactured.

The first and the second mixture were mixed in an appropriate and pharmaceutically usual mixer. To this I -i ~Zlsr*2~ I- II I ILC -1 24 homogenised mixture the third mixture previous indicated was added and correspondingly mixed that long that a homogeneous mixture emerged.

To said homogeneous mixture consisting in said first, second and third mixture, 0,8 g magnesium stearate was added, whereby the magnesium stearate was sieved before over a sieve with a mesh size of 0,3 mm. After being mixed for fifty seconds the hereby emerged mixture was compressed to a tablet weighing 1.000 mg, whereby said tablet was named tablet 8.

4 ,,4 4 4r Example 9 Manufacturing of a tablet with a vitamin mixture as active ingredient 20 A multivitamin mixture (142,8 g) consisting of r 1

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g thiaminenitrate, 0,3 g folic acid, 48,118 g palatinite, g Aerosil 200, 4 g Biogapress 3326 and 6,8 g ethylcellulose was granulated and dried. After the drying and the sieving of the granular powder said sieved granular powder was mixed with a mixture containing 792,4 g glycine and g Kollidon Furthermore a second mixture containing g Polyplasdone XL, g Aerosil 200, 1 g Aspartam powder, Oct 1,5 g Acesulfam K, p* 1 g sodium chloride, g peach aromatic, 2 g citric acid and 4 g magnesium stearate was homogeneously added. Then this mixture was compressed to a tablet weighing 1.000 mg that was named tablet 9.

26 Example Manufacturing of a tablet with the active ingredient acetylsalicylic acid A first mixture containing 85,897 kg glycine and 2 kg Kollidon was manufactured.

From the components 105,263 kg aspirin NCR-P (corresponds to 100 kg 15 acetylsalicylic acid, coated with ethylcellulose), kg tartaric acid, 6 kg Polyplasdone XL, 0,31 kg magnesium stearate, 2 0 2,83 kg talcum microcristalline and 2,7 kg inactive ingredients #4V a second mixture was manufactured, whereby first of all the magnesium stearate and the talcum were mixed manually and added only at the end to a first mixture consisting of aspirin NCR-P, tartaric acid, Polyplasdone XL and the inactive ingredients. Then the total mixture that way 4. 27 manufactured was compressed to a tablet weighing 1.050 mg that was named tablet Example 11 Manufacturing of a conventional tablet with the active ingredient aspirin A first mixture containing 91,16 kg sorbitol and 2 kg Kollidon was manufactured.

.:LI 15 9, 99C S ,O $9t 9 From the components 100 kg crystalline aspirin (acetylsalicylic acid), 5 kg tartaric acid, 6 kg Polyplasdone XL, 0,31 kg magnesium stearate, 2,83 kg talcum microcristalline and 2,7 kg inactive ingredients '.9,99 t1IC 99 I 4 $9 a second mixture was manufactured, whereby first of all the magnesium stearate and the talcum were mixed manually and added only at the end to a first mixture consisting of ft ;I 28 aspirin, tartaric acid, Polyplasdone XL and the inactive ingredients. Then the total mixture that way manufactured was compressed to a tablet weighing 1.050 mg that was named tablet 11.

According to the previous indicated manufacturing instructions in the examples 1 11 further tablets I IX were correspondingly manufactured, whereby said further tablets I IX did not contain glycine. On the contrary the glycine was replaced by a quantity of sorbitol corresponding to the quantity of glycine.

Of the tablets manufactured according to the examples 1 11 and the referent tablets I IX that did not contain 15 glycine, the decomposition times were measured. Heretofore a modified apparatus according to DAB 10 (German Pharmacopoeia) was used.

Said modified apparatus consisted in a rack with a sieving "20 base comprising six cylindrical glass test-tubes. Said tubes, open at the upper end, were closed at the lower end "t only by stainless steel wire, so that the liquid could ,i ,freely enter the tube. Said rack was constantly vertically moved up and down by a motor, whereby the speed was set that way that said rack was moved up and down 28 to 32 times per minute over a way of 50 mm to 60 mm. Hereby said rack was arranged in a 1-liter beaker, whereby said beaker i 29 was filled with 350 ml of cleaned water. Said rack was positioned that way that said tubes had left the water by reaching the extreme point of the upward movement, and by reaching the extreme point of the downward movement they had immersed in the water that deep that all tablets arranged in said tubes were wetted completely.

In each tube one tablet was arranged.

The temperature of the water was set during the measurement on a level between 36 OC and 38 OC.

Then said rack was moved up and down that long till all tablets to be tested were decomposed. The decomposition e 15 time heretofore required was measured, whereby in the following table 1 the uppermost and the lowest 0 decomposition time determined by six measurements are indicated.

0 O 0*L 4 I 4 table 1 Decomposition times of the tablets manufactured according to the examples 1 11 as well as of the tablets I IX (without the addition of glycine) tablet according decomposition time to example in seconds 1 8 2 6 14 3 3 6 4 10 16 8 6 6- 9 S15 7 9 -12 Ctti EE 8 8 -12 S9 12 18 3 8 Ott 4 referent tablets t 11 60 I 60 II 70 III 60 IV 90 120 V 90 100 _~-1low _r-t.

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60 80 70 80 100 A taste- and acceptance-test was made with 30 persons who for several days took a trade-usual tablet (according to example 11) or an externally identical tablet-shaped remedy (according to example 10) that differed from the known remedies in the way that it contained additionally the quantity of glycine indicated in example 10. The persons could not distinguish both tablets from their exterior.

Each person received the trade-usual tablet, as well as the above mentioned tablet-shaped remedy.

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44 4 9 99 9r r*4 c All the 30 persons conformably reported how pleasant and easy the use of the tablet mixed with glycine (according to example 10) was.

iI 0tL f C 1 0 In particular the probationers conformably confirmed that compared to the conventional drug, the tablet mixed with glycine was regarded as extremely positive and pleasant during the use and chewing in the mouth. The typical and permanent conglutination of the known tablet and its components on the palate, teeth and gums was not observed it S32 during the application and use of the tablet mixed with glycine. Also this tablet dissolved a lot faster which was considered as very comfortable.

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Claims

1. A pharmaceutical, orally applicable composition, whereby said solid composition contains at least one active ingredient selected from the group consisting of an analgesic, an antirheumatic agent or a mixture thereof, at least one disintegrant selected from the group consisting of starch, a starch derivative, cellulose, a cellulose derivative, alginic acid, an alginic acid derivative, casein, a casein derivative, an insoluble polyvinylpyrrolidone and mixtures thereof, as well as at least one usual pharmaceutical additional ingredient, whereby said composition furthermore contains at least one ingredient accelerating the decomposition of said composition in the mouth or in a liquid, whereby this ingredient is a water-soluble amino acid, a water-soluble amino acid derivative and/or a water-soluble salt of an amino acid and whereby said composition contains said ingredient in such a concentration that said composition decomposes in the mouth or in a liquid within one second up to thirty seconds.

2. The pharmaceutical composition according to claim 1, characterised in that 15 said ingredient is glycine, a glycine derivative and/or a glycine salt.

3. The pharmaceutical composition according to claim 1, characterised in that SC., said ingredient is proline, hydroxy proline and/or lysine, a salt and/or a derivative 0" t thereof.

4. The pharmaceutical composition according to any one of the preceding claims, S 20 characterised in that said comp,.ition contains said ingredient in a concentration between 4 1% by weight and 90% by weight. The pharmaceutical composition according to claim 4, characterised in that said composition contains said ingredient in a concentration between 20% by weight and by weight, corresponding to said composition ready to use.

S 25

6. The pharmaceutical composition according to any one of the preceding claims, characterised in that said composition contains said disintegrant in a concentration between 1% by weight and 50% by weight, corresponding to said composition ready to use.

7. The pharmaceutical composition according to claim 6, characterised in that said composition contains said disintegrant in a concentration between 3 by weight and by weight, corresponding to said composition ready to use.

8. The pharmaceutical composition according to any one of the preceding claims, characterised in that said composition contains said at least one active ingredient as active ingredient particles uniformly dispersed in said solid composition.

9. The pharmaceutical composition according to any one of the preceding claims, characterised in that said active ingredient is an active ingredient on the base of a pyrazolone compound, a salicylic acid compound, a phenylbutazone compound, an anthranilic acetic compound, an aryl-acetic compound and/or an arylpropionic acid R ompound. 4UZ~ [N:UIBHIO182:KBM r- ~L~t:il U 34 I

10. The pharmaceutical composition according to any one of the preceding claims, characterised in that said active ingredient is paracetamol, acetylsalicylic acid, ketoprofen, ibuprofen and/or diclofenac-sodium.

11. The pharmaceutical composition according to any one of the preceding claims, characterised in that said composition contains the at least one active ingredient in a concentration between 1% by weight and 50% by weight, corresponding to the composition ready to use.

12. The pharmaceutical composition according to claim 11, characterised in that said composition contains the at least one active ingredient in a concentration between o1 15% by weight and 40% by weight, corresponding to the composition ready to use.

13. The pharmaceutical composition according to any one of the preceding claims, characterised in that said composition contains at least one hydrophilic active ingredient provided with a hydrophobic coating layer and/or at least one hydrophilic active ingredient being embedded in a hydrophobic matrix.

14. The pharmaceutical cc~nposition according to claim 13, characterised in that said hydrophobic coating layer and/or said matrix comprise shellac, stearic acid, gelatine, zein, gum arabic, cellulose derivatives, polymer acrylic acid derivatives and/or polymer vinylacetates.

The pharmaceutical composition according to any one of the preceding claims, 20 characterised in that said solid composition contains as additional ingredient between 0% by weight and 60% by weight bulkages and/or binders, between 0% by weight and Sby weight of at least one of povidone, sugar, sugar alcohols, polyethyleneglycol as well as usual sweetening agents and/or aromatics.

16. The pharmaceutical composition according to any one of the preceding claims, characterised in that said composition has the form of a tablet or a granular powder.

"17. A pharmaceutical, orally applicable composition, whereby said solid composition contains at least one active ingredient, at least one disintegrant, as well as at least one usual pharmaceutical additional ingredient, substantially as hereinbefore described with reference to any one of the examples. Dated 11 August, 1998 Rh6ne-Poulenc Rorer GmbH Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON t L v ,ZI IN\ULBHl0182:KBM Pharmaceutical, Orally Applicable Composition Abstract A pharmaceutical, orally applicable composition is described, whereby the solid composition contains at least one active ingredient, at least one disintegrant, as well as at least one usual pharmaceutical additional ingredient. Furthermore said composition contains at least one 0" ingredient that accelerates the decomposition of said 10 composition in the mouth or in a liquid, whereby said ingredient is a water-soluble amino acid, a water-soluble amino acid derivative and/or a water-soluble amino acid salt. :ct c I C